Understanding the process of fibrosis in Duchenne muscular dystrophy

Abstract

Fibrosis is the aberrant deposition of extracellular matrix (ECM) components during tissue healing leading to loss of its architecture and function. Fibrotic diseases are often associated with chronic pathologies and occur in a large variety of vital organs and tissues, including skeletal muscle. In human muscle, fibrosis is most readily associated with the severe muscle wasting disorder Duchenne muscular dystrophy (DMD), caused by loss of dystrophin gene function. In DMD, skeletal muscle degenerates and is infiltrated by inflammatory cells and the functions of the muscle stem cells (satellite cells) become impeded and fibrogenic cells hyperproliferate and are overactivated, leading to the substitution of skeletal muscle with nonfunctional fibrotic tissue. Here, we review new developments in our understanding of the mechanisms leading to fibrosis in DMD and several recent advances towards reverting it, as potential treatments to attenuate disease progression.

Figure 1

Crosstalk between TGFβ signaling and the renin-angiotensin system in fibrosis. TGFβ can signal via its canonical pathway, involving Smad proteins, or through several alternative pathways such as the p38 MAPK signaling or the RAS/ERK MAPK signaling pathways. Both canonical and alternative pathways lead to expression of molecules implicated in fibrosis such as CTGF or PAI-1. Similarly, Ang II signals through AT1 or AT2 and can also activate Smad proteins and the p38 MAPK signaling pathway, leading to increased expression of profibrotic genes. Ang 1–7 has an opposite effect, inhibiting the canonical TGFβ pathway. Antifibrotic molecules inhibiting RAS or the TGFβ signaling are indicated in red.